The overall objective of this Independent Scientist Career Development (K02) application is to support the continued career development of the candidate who is a quantitative geneticist with specialized expertise in addiction and to facilitat her efforts to build a program of research into the role of genetic influences on cannabis involvement by integrating methodologies from twin epidemiological, candidate gene and genomewide association studies. Cannabis is the most commonly used illicit drug in developed nations and both cannabis use and misuse have undergone increase in the past 2 years. Yet, far too little is known of its genetic underpinnings. Ongoing work by the candidate has delineated how latent (via analysis of twin data) and measured (via linkage, candidate gene and genomewide association) genetic influences shape vulnerability to cannabis involvement. This proposal builds on that existing framework by incorporating training in (a) endocannabinoid pharmacology; (b) multivariate statistical methods that integrate pharmacological evidence with human genetics studies; and (c) the relevance of genetic influences on treatment-related outcomes, to allow the candidate to recast the extant literature on the genetic epidemiology of cannabis involvement in a biologically relevant and statistically meaningful context. Cross-disciplinary collaboration with experts and application of newly acquired knowledge to ongoing data analysis will allow this K02 to significantly expand on our existing knowledge of the genetics of cannabis involvement. From a mental health perspective, findings from this proposal address a key component of the challenges imposed by escalating rates of cannabis use - how genetic pathways shape its etiology. They have the potential to provide a refined understanding of the biology underlying cannabis involvement while simultaneously studying its relevance in treatment settings. The specific goals of this proposal are to (a) use twin modeling to delineate the role of genetic influences on stages of cannabis involvement from opportunity to use to the development of cannabis use disorders; (b) use knowledge from endocannabinoid pharmacology to identify which specific aspects of cannabis involvement are associated with candidate genes (e.g. CNR1); (c) to use novel statistical methods to conduct and efficiently interpret genomewide association studies; and (d) to apply the findings from prior aims to treatment settings and delineate the role of genomic risk on treatment outcomes. This K02 will also support the candidate's vision to provide mentorship to the next cohort of addiction researchers through provision of training in methodologies specific to addiction-related phenotypes. PUBLIC HEALTH RELEVANCE: Cannabis is the most commonly used illicit drug and the most prevalent illicit drug use disorder in developed nations. Furthermore, during 2009-2010, rates of lifetime, past year and daily cannabis use increased in 8th, 10th and 12th graders in the U.S., making it an emerging public health challenge. Despite evidence for heritable influences, there is little known of the genetic etiology of cannabis involvement. This proposal uses twin epidemiological and genomic methods to investigate the genetic underpinnings of cannabis involvement. Results will provide a framework for the biological basis for cannabis involvement and will be utilized in treatment seeking samples to investigate the influence of genetic vulnerability in course of treatment.